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• Biallelic tumor suppressor loss and DNA repair defects in de novo small cell prostate cancer

  Small cell prostatic carcinoma (SCPC) is an aggressive pathology that is managed similar to small cell lung cancer. SCPC can evolve from prostatic adenocarcinoma in response to androgen deprivation therapy but in rare cases is present at initial cancer diagnosis. The molecular etiology of de novo SCPC is incompletely understood due to the scarcity of tumor tissue and the brief life expectancy of patients. Through a retrospective search of our regional oncology pharmacy database, we identified 18 patients diagnosed with de novo SCPC between 2004 and 2017. Ten patients had pure SCPC pathology and the remainder had some admixed adenocarcinoma foci, but all were treated with first line platinum-based chemotherapy. Median overall survival was 28 months. We performed targeted DNA sequencing, whole exome sequencing and mRNA profiling on formalin-fixed paraffin embedded archival tumor tissue. We observed frequent biallelic deletion and/or mutation of tumor suppressors TP53, RB1 and PTEN, similar to treatment related SCPC. Indeed, at the RNA level pure de novo SCPC closely resembled treatment-related SCPC. However, five patients had biallelic loss of DNA repair genes including BRCA1, BRCA2, ATM and MSH2/6: potentially underlying the high genomic instability of this rare disease variant. Two patients with pure de novo SCPC harbored ETS gene rearrangements to androgen-driven promoters, consistent with evolution of de novo SCPC from an androgen-driven ancestor. Overall, our results reveal a highly aggressive molecular landscape underlies this unusual pathologic variant, and propose opportunities for targeted therapy strategies in a disease with few treatment options.

  Study EGAS00001003007

• A Phase II Clinical Trial of the PARP Inhibitor Talazoparib in BRCA1 and BRCA2 Wild-Type Patients

  The Talazoparib Beyond BRCA (TBB), a phase II proof-of-concept clinical trial, was designed to test the efficacy of talazoparib, a potent, orally bioavailable PARP inhibitor, with an established Phase II recommended dose, in the treatment of advanced BRCA wildtype (WT), HER2-negative breast cancer and other solid tumors with homologous recombination (HR) deficiency. Eligible patients had advanced HER2-negative breast cancer or other solid tumors with a germline or somatic mutation in a gene linked to the HR pathway. Patients identified as harboring a deleterious or suspected deleterious germline or somatic mutation in the HR pathway were treated with single agent talazoparib until disease progression. Primary and metastatic tumor samples were sequenced with panel sequencing and exome sequencing to detect commonly mutated genes and those associated with DNA repair deficiency. In addition, ctDNA was sequenced at baseline and progression. Fastq files for tumor and ctDNA sequencing are deposited. 

  Study phs002803

• Effect of ETS2 modulation on chromatin accessibility and enhancer activity in inflammatory (TPP) macrophages

  This dataset consists of H3K27ac ChIP-seq and ATAC-seq in primary human macrophages following modulation of ETS2 expression. There are three datasets: H3K27ac ChIP-seq in ETS2-edited and unedited inflammatory (TPP) macrophages, H3K27ac ChIP-seq in ETS2-overexpressing and control M0 macrophages, and ATAC-seq in ETS2-edited and unedited inflammatory macrophages. For editing experiments, monocytes were transfected with CRISPR-Cas9 ribonucleoproteins containing a gRNA that was validated to edit ETS2, or a non-targeting control gRNA. Inflammatory macrophage differentiation was performed using conditions that model chronic inflammation (TPP): 3 days GM-CSF (50ng/mL) followed by 3 days GM-CSF, TNFa (50ng/mL), PGE2 (1mg/mL), and Pam3CSK4 (1mg/mL). For overexpression experiments, controlled overexpression of ETS2 mRNA or control mRNA (an equivalent amount of mRNA encoding the reverse complement of ETS2 – thereby controlling for the quantity, length and purine/pyrimidine composition of the transfected RNA but with a transcript that would not be translated) was induced in resting, non-activated (M0) macrophages by transfecting 500ng mRNA. To minimise non-specific activation due to the transfected RNA, in vitro transcription was performed using co-transcriptional capping (to minimise uncapped products), and incorporating modified, minimally immunogenic nucleotides (replacing uridine with N1-methyl-pseudouridine and cytidine with methylcytidine). After 18 hours, transfected cells were were activated with low dose LPS and harvested 6 hours later. For H3K27ac ChIP-seq, cells were harvested, cross-linked, quenched, lysed, and sheared. Immunoprecipitation of histone-DNA complexes was performed overnight at 4C with rotation using an anti-H3K27ac antibody and the SimpleChIP Plus Sonication ChIP kit (Cell Signaling Technology). Following reverse cross-linking, 50ng of immunoprecipitated DNA or input DNA were used to prepare sequencing libraries using the iDeal Library Preparation kit (Diagenode), according to manufacturer instructions. 10 PCR cycles were used for the amplification step and size selection was not performed. The quality and molarity of all libraries was assessed using a BioAnalyzer 2100 (Agilent) and the libraries were sequenced on an Illumina NovaSeq 6000. Raw data are provided as raw and aligned sequencing reads from H3K27ac-bound DNA and the input chromatin. ATAC-seq in TPP macrophages was performed using the Omni-ATAC protocol (Corces et al 2017) with the following modifications: cell number was increased to 75,000 cells, cell lysis time was increased to 5 minutes; volume of Tn5 transposase in the transposition mixture was doubled; duration of the transposition step was extended to 40 minutes. Sequencing libraries were prepared by PCR with the NEBNext Ultra II Q5Master Mix (NEB) as described previously (Corces et al 2017). Amplified libraries were cleaned using AMPure XP beads (Beckman Coulter). Sequencing reads were trimmed using TrimGalore! (Phred score 24), filtered to remove reads < 20 bp and aligned to the human genome (hg19) using Burrows-Wheeler Aligner (BWA). Aligned reads were converted to BAM files, sorted and indexed using SAMtools (Li et al, 2009). PCR duplicates and unmapped reads were removed, and the resulting BAM files were re-sorted and indexed. Raw data are provided as 100 bp paired-end Illumina reads from n = 3 donors for each experiment. BAM files are also provided.

  Study EGAS50000000109

• Sensitive Monogenic Noninvasive Prenatal Diagnosis by Targeted Haplotyping

  During pregnancy, cell-free DNA (cfDNA) in maternal blood encompasses a small percentage of cell-free fetal DNA (cffDNA), an easilyaccessible source for determination of fetal disease status in risk families through non-invasive procedures. In case of monogenic heritabledisease, background maternal cfDNA prohibits direct observation of the maternally inherited allele. Non-invasive prenatal diagnostics(NIPD) of monogenic diseases therefore relies on parental haplotyping and statistical assessment of inherited alleles from cffDNA,techniques currently unavailable for routine clinical practice. Here, we present monogenic NIPD (MG-NIPD), which requires a bloodsample from both parents, for targeted locus amplification (TLA)-based phasing of heterozygous variants selectively at a gene of interest.Capture probes-based targeted sequencing of cfDNA from the pregnant mother and a tailored statistical analysis enables predicting fetalgene inheritance. MG-NIPD was validated for 18 pregnancies, focusing on CFTR, CYP21A2, and HBB. In all cases we could predict theinherited alleles with &gt;98% confidence, even at relatively early stages (8 weeks) of pregnancy. This prediction and the accuracy ofparental haplotyping was confirmed by sequencing of fetal material obtained by parallel invasive procedures. MG-NIPD is a robustmethod that requires standard instrumentation and can be implemented in any clinic to provide families carrying a severe monogenicdisease with a prenatal diagnostic test based on a simple blood draw.

  Study EGAS00001002622

• Extracorporeal Life Support Survival in a Pediatric Hematopoietic Cellular Transplant Recipient with Presumed Graft Versus Host Disease-Related Fulminant Myocarditis

  We report the case of a 15-year-old female with hypodiploid pre-B acute lymphoblastic leukemia status post allogeneic hematopoietic stem cell transplantation (HCT) from a matched unrelated male donor who presented on transplant day +75 with cardiac arrest due to ventricular fibrillation associated with fulminant myocarditis. Using conventional diagnostics, an exhaustive search for microbial pathogens in the heart biopsy as well as nasopharynx, blood, urine, and endotracheal aspirate was performed but did not uncover a candidate pathogen. The family consented to a research study for the use of unbiased next-generation genomic sequencing for pathogen identification in the myocardial biopsy. DNA sequencing was performed on 1.5 x 108 sequencing pairs and no microbial pathogens were identified. Interestingly, a significant component of Y-chromosomal human DNA was identified, suggesting infiltration of at least 10 donor leukocytes per host cell. This finding is grossly consistent with the lymphocyte:myocyte ratio in the biopsy according to visual inspection at 40x magnification. This case merits discussion due to (1) her survival after 17 days of veno-arterial extracorporeal life support (ECLS) and (2) the possibility of cardiotropic graft versus host disease (GVHD).

  Study phs001336

• Cholangiocarcinoma

  Arcagen is an EORTC/SPECTA pan-European project that aims to recruit 1000 rare cancer patients from different tumour domains of EURACAN. This study collected samples from advanced or metastatic rare cancer from patients older than 12, and analysed them using Foundation Medicine next-generation sequencing (NGS) panels (FoundationOne CDx for FFPE samples or FoundationOne Liquid CDx for blood samples). Here we are submitting two datasets that contain NGS files from gastrointestinal rare cancers (n=119): - Dataset 2 (87 patients): Intra-hepatic cholangiocarcinoma (n=47), Extra-hepatic, cholangiocarcinoma (n=16), Not specified Cholangiocarcinoma (n=9), Small bowel adenocarcinoma (n=6) and other rare GI cancer (n=9)

  Dataset EGAD00001008968

• Clonal Evolution of Pre-Leukemic Hematopoietic Stem Cells Precedes Human Acute Myeloid Leukemia

  Acute myeloid leukemia is an aggressive clonal malignancy of the bone marrow that is the direct result of sequential acquisition of mutations in a single lineage of cells. In this study, we investigate a model in which this mutational acquisition occurs serially in long-lived self-renewing hematopoietic stem cells eventually resulting in frank acute myeloid leukemia. Coding mutations in multiple AML patients were identified using exome sequencing followed by sanger sequencing validation. The level of these mutations was then assessed in residual hematopoietic stem cells from each patient using targeted deep sequencing. These population-level estimates of mutant allele burden were then validated in single cell assays targeted to the identified mutations. This allowed for determination of the order of acquisition of the mutations that preceded the development of the leukemia. The results of this study identify pre-leukemic hematopoietic stem cell clones that could contribute to patient relapse and outcome.

  Study phs000549

• Orthotopic Patient-Derived Xenografts of Pediatric Solid Tumors

  Pediatric solid tumors arise from endodermal, ectodermal, or mesodermal lineages. Although the overall survival of children with solid tumors is 75%-80%, that of children with recurrent disease is below 30%. To capture the complexity and diversity of pediatric solid tumors and establish new models of recurrent disease, we developed a protocol to produce orthotopic patient-derived xenografts (O-PDXs) at diagnosis, recurrence, and autopsy. Tumor specimens were received from 168 patients, and 64 O-PDXs were established for 12 types of pediatric solid tumors. The origins of the O-PDX tumors were reflected in their gene-expression profiles and epigenomes. Genomic profiling of the tumors, including detailed clonal analysis, was performed to determine whether the clonal population in the xenograft recapitulated the patient’s tumor. We identified several drug vulnerabilities and showed that the combination of a WEE1 inhibitor (AZD1775), irinotecan, and vincristine can lead to complete response in multiple rhabdomyosarcoma O-PDX tumors in vivo.

  Study EGAS00001002528

• Biallelic DICER1 mutations in sporadic pleuropulmonary blastoma

  Pleuropulmonary blastoma (PPB) is an extremely rare pediatric malignancy in the lung, whose pathogenesis is poorly understood, except for recent reports of frequent germline heterozygous DICER1 mutations. To investigate the genetic basis of PPB, we performed whole-exome sequencing in 7 representative PPB cases, followed by targeted deep sequencing in 12 cases with PPB. DICER1 mutations were found in 11/12 cases. Biallelic DICER1 mutations were common in PPB, in which RNase IIIb domain mutations were found in all cases with or without nonsense/frameshift mutations and were somatic in all evaluable cases. A majority of cases had mutated DICER1 alleles in germline with or without an additional somatic mutation in the remaining allele, while other cases had exclusively somatic mutations involving the RNase IIIb domain. TP53 deletions/mutations were detected in 8/12 cases. Our results highlight a unique role of the RNase IIIb domain mutations and TP53 inactivation in PPB pathogenesis.

  Study EGAS00001000662

• Fibroblast heterogeneity drives metastatic spread in breast cancer through distinct mechanisms

  The major cause of death among breast cancer patients is metastatic dissemination, suggesting that understanding the mechanisms driving this process remains an unmet medical need. Here, by concomitantly using 5 markers, we identify 4 Carcinoma-Associated Fibroblasts (CAF) subsets in primary tumors and corresponding metastatic lymph nodes (LN). Two CAF subsets, called CAF-S1 and CAF-S4, correlate with the proportion of cancer cells in invaded LN and exert distinct functions in tumor cell spread. CAF-S1 promote cancer cell migration and initiates an epithelial to mesenchymal transition through a CXCL12 / TGFb positive loop. For their part, the highly contractile CAF-S4 foster cancer cell motility and invasion in 3-dimensional matrix via Notch pathway activation. Finally, CAF-S1 and CAF-S4 accumulation in LN is a new prognostic factor at diagnostic, independent of breast cancer subtypes and LN status, strengthening the validity of our findings in human breast cancer pathophysiology.

  Study EGAS00001003238